A cell may become cancerous through transformation of a portion of its DNA into an oncogene, i.e., a gene that on activation leads to the formation of malignant tumor cells. Many oncogenes encode proteins that are aberrant tyrosine kinases capable of causing cell transformations. Alternatively, the overexpression of a normal proto-oncogenic tyrosine kinase may result in proliferative disorders, sometimes of a malignant phenotype.
Receptor tyrosine kinases are large enzymes spanning the cell membrane and having an extracellular binding domain for growth factors (such as epidermal growth factor), a transmembrane domain, and an intracellular portion that functions as a kinase to phosphorylate specific tyrosine residues in proteins, hence to influence cell proliferation. Such tyrosine kinases are often aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancers (such as colon, rectal and stomach cancers), leukemia, and ovarian, bronchial or pancreatic cancer. It has also been shown that epidermal growth factor receptor (EGFR), which possesses tyrosine kinase activity, is mutated and/or overexpressed in many human cancers, such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophasgeal, gynecological, and thyroid tumors.
Accordingly, it has been recognized that inhibitors of receptor tyrosine kinases are useful as selective inhibitors to the growth of mammalian cancer cells. For example, erbstatin, a tyrosine kinase inhibitor selectively attenuates the growth in athymic nude mice of a transplanted human mammary carcinoma that expresses epidermal growth factor receptor tyrosine kinase (EGFR), but it is not effective on inhibiting the growth of another carcinoma that does not express the EGF receptor.
Various compounds, such as styrene and quinazoline derivatives, have been reported to possess anti-cancer properties, as a result of their tyrosine kinase inhibitory properties, (see, e.g., EP 0 566 226 A2, EP 0 602 851 A1, EP 0 635 507 A1, EP 0 635 498 A1 and EP 0 520 722 A1) (U.S. Pat. No. 5,747,498).
EGF type receptor tyrosine kinases are also implicated in various non-malignant proliferative disorders, and therefore inhibitors of EGF type receptor tyrosine kinases have been reported to be useful for the treatment of non-malignant diseases of excessive cellular proliferation, such as psoriasis (where TGFα is believed to be the most important growth factor), benign prostatic hypertrophy (BPH), atherosclerosis, and restenosis.
Quinazoline derivatives, including the ones bearing an anilino substituent at the 4-position, an alkoxy substituent at the 7-position, and an alkoxy substituent at the 6-position, have been disclosed to possess anti-cancer activities (see, e.g., U.S. Pat. No. 5,770,599, U.S. Pat. No. 5,747,498, EP 1,110,953, EP 8 17,775, U.S. Pat. No. 6,476,040, and Jänne, P. A. et al., Nat. Rev. Drug Discov., 2009, 8(9):709-23). In particular, Erlotinib, also known as [6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)-amine or N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine, is an inhibitor of EGF receptor tyrosine kinases approved in the United States and Europe for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). Erlotinib is particularly effective for the patients who have failed in at least one prior chemotherapy regimen. A combination therapy of Erlotinib with a nucleoside analog, gemcitabine, has also been approved in the United States for the treatment of metastatic pancreatic cancer. Erlotinib, alone or in combination with other agents, is also being investigated in the clinical trials for the treatment of a variety of cancers, including, but not limited to lung cancer, pancreatic cancer, astrocytoma, renal cancer, head and neck cancer, breast cancer, bladder cancer, ovarian cancer, colorectal cancer, prostate cancer, cervical cancer, thymoma cancer, liver cancer and gastric cancer. Erlotinib has also been thought to be useful in the treatment of benign prostate hyperplasia (BPH).
Tykerb (Lapatinib), another 4-(substituted phenylamino) quinazoline analog, is used as a second-generation treatment for solid tumor. As a dual-HER1/HER2 tyrosine kinase inhibitor, it is believed to be more effective for the patients who are naturally HER1 resistant or have acquired such resistance. Tovok (BIBW 2992), another 4-(substituted phenylamino) quinazoline analog, is also an anti-cancer agent, which has entered Phase III clinical trials for non-small cell lung carcinoma and phase II trials for breast, prostate, and head and neck cancers, as well as glioma. It has a chemically reactive group to irreversibly modify the target residues to increase the efficacy for the treatment of cancer patients. As another example of irreversible anti-cancer agents, CUDC-101, a multiple inhibitor for EGFR, HER2 and histone deacetylase is also in clinical trials for different kinds of cancers.
Although the above examples have shown that the 4-(substituted phenylamino) quinazoline represents a privileged core structure, based on which useful anticancer agents, such as Erlotinib, Gefitinib and Lapatinib, have been developed (see, e.g., Zhang, J. et al., Nat. Rev. Cancer, 2009, 9(1):28-39), extensive research is still being conducted to discover novel therapeutic agents containing the same core structure. There is a continuing need for the development of new anti-cancer agents that are more effective, yet less toxic, for the treatment of the aforementioned diseases and conditions.